2,6-diisopropylphenol is a known parenteral, short-acting general anaesthetic. It is widely used in the form of injection by anaesthetists for induction and maintenance of anaesthesia and for sedation.
Similarly, to most of the injectable anaesthetics, 2,6-diisopropylphenol has lipophilic character. This means good lipid solubility, which is necessary for the anaesthetic agent to be able to cross the blood-brain barrier. Unfortunately, the lipophilic character of the compound results that it is insoluble in and immiscible with water and thus an intravenous injection can be formulated very difficultly. Although the compound of 2,6-diisopropylphenol can be well solved in organic solvents like tetrahydrofuran, such solvents however cannot be taken into consideration for formulating a drug.
In the past efforts were made to prepare a solubilized injection. A formulation containing 2,6-diisopropylphenol and surfactant Cremophor EL.RTM. (trademark for a polyoxyethylene castor oil derivative) seemed to be acceptable but later anaphylactic reactions were reported (Laxenare MC et al, Lancet 1988 ii. 739-740).
The present commercially available formulation of 2,6-diisopropylphenol is in the form of a white, soybean oil-in-water emulsion, which is stabilized by lecithin (Diprivan). Sterile pharmaceutical compositions of 2,6-diisopropylphenol and their use in inducing anaesthesia are described in U.S. Pat. Nos. 4,056,635, 4,452,817 and 4,798,846.
There were further attempts made to prepare better formulations but all ol them were based on a kind of emulsion. Thus the U.S. Pat. No. 5,714,520 describes a composition containing edetate to prevent the growth of micro organism. It has some advantage over the currently marketed product but this is also a soybean oil-in-water emulsion with lecithin as stabilizator. The U.S. Pat. No. 5,637,625 discloses a phospholipid-coated micro-droplet formulations, which prevent the fat overload and is shown to be bactericid. The PCT Patent application No. WO 98/53805 describes a clear, injectable formulation of 2,6-diisopropylphenol with bile acid and lecithin.
These emulsion formulations have some advantages over the currently marketed formulation nevertheless certain problems arising from the emulsion form and its ingredients remained. The ingredients are natural products (soybean oil, lecithin) which require strict quality control and monitoring. They are good source, as nutrient, for growth of micro-organisms, consequently strict controls for aseptic production and filling are required. Monitoring the particle size of the emulsion and keeping the product in a homogenous form as well, need complicated manufacturing technology. In a few cases hyperlipidemia caused by the fat overload in patients undergoing long term sedation was observed.
Therefore there is still a need for a stable, dose flexible anaesthetic solution, which can be conveniently filtered, sterilized and is free from all the limitations derived from the characters of emulsion formulation and its ingredients.